NM_080425.4:c.2322C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BA1

The NM_080425.4(GNAS):c.2322C>T(p.Ile774Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,612,326 control chromosomes in the GnomAD database, including 209,225 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 26067 hom., cov: 28)

Exomes 𝑓: 0.49 ( 183158 hom. )

Consequence

GNAS
NM_080425.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.364

Publications

128 publications found

Variant links:

Genes affected

GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]

GNAS Gene-Disease associations (from GenCC):

McCune-Albright syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
progressive osseous heteroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohypoparathyroidism type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudohypoparathyroidism type 1C
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudopseudohypoparathyroidism
Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
pseudohypoparathyroidism type 1A
Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GNAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6

Variant 20-58903752-C-T is Benign according to our data. Variant chr20-58903752-C-T is described in ClinVar as Benign. ClinVar VariationId is 197681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.364 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNAS	NM_080425.4 link	c.2322C>T	p.Ile774Ile	synonymous_variant	Exon 5 of 13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.393C>T	p.Ile131Ile	synonymous_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	c.*299C>T		3_prime_UTR_variant	Exon 5 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000371100.9 link	c.2322C>T	p.Ile774Ile	synonymous_variant	Exon 5 of 13	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.393C>T	p.Ile131Ile	synonymous_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2 link	c.2325C>T	p.Ile775Ile	synonymous_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.2280C>T	p.Ile760Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12 link	c.396C>T	p.Ile132Ile	synonymous_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7 link	c.351C>T	p.Ile117Ile	synonymous_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6 link	c.219C>T	p.Ile73Ile	synonymous_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.219C>T	p.Ile73Ile	synonymous_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.219C>T	p.Ile73Ile	synonymous_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.174C>T	p.Ile58Ile	synonymous_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7 link	c.*299C>T		3_prime_UTR_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7 link	c.*254C>T		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000461152.6 link	c.*349C>T		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes

AF:

0.571

AC:

86368

AN:

151368

Hom.:

26014

Cov.:

show subpopulations

Gnomad AFR

AF:

0.750

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.594

Gnomad ASJ

AF:

0.629

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.577

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.682

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.623

GnomAD2 exomes

AF:

0.543

AC:

136663

AN:

251484

AF XY:

0.539

show subpopulations

Gnomad AFR exome

AF:

0.758

Gnomad AMR exome

AF:

0.619

Gnomad ASJ exome

AF:

0.631

Gnomad EAS exome

AF:

0.649

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.491

Gnomad OTH exome

AF:

0.557

GnomAD4 exome

AF:

0.495

AC:

722387

AN:

1460840

Hom.:

183158

Cov.:

AF XY:

0.497

AC XY:

361154

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.768

AC:

25692

AN:

33468

American (AMR)

AF:

0.617

AC:

27608

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.630

AC:

16467

AN:

26130

East Asian (EAS)

AF:

0.603

AC:

23944

AN:

39694

South Asian (SAS)

AF:

0.568

AC:

48968

AN:

86248

European-Finnish (FIN)

AF:

0.373

AC:

19910

AN:

53408

Middle Eastern (MID)

AF:

0.696

AC:

4015

AN:

5766

European-Non Finnish (NFE)

AF:

0.471

AC:

523200

AN:

1111052

Other (OTH)

AF:

0.540

AC:

32583

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

21183

42366

63550

84733

105916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15598

31196

46794

62392

77990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.571

AC:

86486

AN:

151486

Hom.:

26067

Cov.:

AF XY:

0.568

AC XY:

42026

AN XY:

74016

show subpopulations

African (AFR)

AF:

0.751

AC:

30948

AN:

41226

American (AMR)

AF:

0.594

AC:

9051

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.629

AC:

2180

AN:

3464

East Asian (EAS)

AF:

0.649

AC:

3320

AN:

5114

South Asian (SAS)

AF:

0.577

AC:

2753

AN:

4774

European-Finnish (FIN)

AF:

0.357

AC:

3762

AN:

10524

Middle Eastern (MID)

AF:

0.685

AC:

200

AN:

292

European-Non Finnish (NFE)

AF:

0.483

AC:

32774

AN:

67852

Other (OTH)

AF:

0.627

AC:

1319

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1696

3392

5088

6784

8480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.530

Hom.:

75891

Bravo

AF:

0.598

Asia WGS

AF:

0.644

AC:

2238

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 13, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ile774Ile in exon 5 of GNAS: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 81.39% (1076/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs7121). -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10406816, 17388805) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoparathyroidism type 1C

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive osseous heteroplasia

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoparathyroidism type I A

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoparathyroidism type 1B

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudopseudohypoparathyroidism

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.5

(source)

DANN

Benign

0.89

PhyloP100

-0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over